The goal of this proposal is to advance an orally bioavailable first-in-class somatostatin receptor subtype-4 selective drug candidate with disease-modifying attributes for the treatment of Alzheimer's disease (AD). The hit compound has been validated to enhance learning and memory in mouse models of AD and cognitive decline, with a reduction of beta-amyloid (A) oligomer levels within the brain. Our program has now advanced to lead optimization, which is accomplished through enhancement of drug-like properties of the lead series in tandem with well-defined advancement criteria, respective to modeling, in vitro screens and in vivo/ex vivo validation. This study will be accomplished via three specific aims. Based on outcomes within each aim, additional design adjustments and testing may be performed. Aim-1: Design and synthesis. Rational drug design strategies employing iterative in silico modeling, synthesis, and structure-activity relationship (SAR) studies will be conducted to enhance potency and selectivity, reduce potential toxicity, and enhance physiochemical properties for oral bioavailability. Synthetic methods will be further developed and applied to iterative and parallel medicinal chemistry where appropriate. Aim-2: In vitro screens. Using established in vitro methods, critical properties (i.e. solubility, receptor affinity and selectivity, activity, plasma binding, stability, permeability, and toxicity potential will be assessed in a sequential manner to delineate compound viability. Aim-3: In vivo/ex vivo assessments. Compounds meeting necessary criteria will be advanced to pharmacokinetic evaluations (i.v. and p.o.) for further delineation and identification of a primary lead. This lead will be tested via chronic p.o. administration in the 3xTg mouse model of AD at age-dependent intervals that coincide with critical periods of neuropathological development and learning/memory decline. Dosing range will be determined from pharmacokinetic data. Delineation of lead compound impact on learning and memory will be assessed via Morris water-maze, T-maze, and object recognition testing. Following final behavioral testing, cortical and hippocampal tissues will be evaluated to delineate changes in critical proteins/enzymes associated with AD pathology and proposed drug mechanism. This study will culminate in the advancement of a first-in-class AD drug candidate to the next stage of development. The aims of this study address priorities of National Institutes of Health, specific to drug discovery for nervous system disorders respective to drug-candidate lead optimization: FOA number: PAR-13-048.